Host Sensing of Microbiota-Associated Metabolites in Gastrointestinal Graft-Versus-Host Disease: Cell-Specific Mechanisms and Pharmacological Opportunities

Background: Gastrointestinal graft-versus-host disease (GI-GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Conditioning directly injures the intestinal epithelium, whereas antibiotics, nutritional disruption, and immunosuppression remodel the intestinal ecosystem; together, these exposures are associated with loss of obligate anaerobes and altered availability of microbiota- associated metabolites. This review examines how host tissues sense these metabolic changes and translate them into divergent biological outcomes. Methods: We integrate evidence on directly produced microbial metabolites, including short-chain fatty acids, tryptophan-derived indoles, and desaminotyrosine, as well as microbially modified bile acids, host–microbial co-metabolites such as trimethylamine N-oxide, and emerging microbiota-associated compounds. We then examine receptor-mediated pathways involving FFAR2/3, HCAR2, AhR, PXR, FXR, TGR5, and VDR, as well as receptor-independent mechanisms such as HDAC inhibition and mTORC1-STING-dependent regeneration. Results: We propose that metabolite activity in GI-GVHD is determined not by abundance alone, but by chemical form, concentration, tissue distribution, sensor identity, responding cell type, and disease stage. This framework explains how a metabolite may reinforce epithelial tolerance while promoting inflammatory myeloid or donor T-cell programs in another compartment. We further evaluate postbiotic replacement, receptor modulation, precision nutrition, defined microbial consortia, and fecal microbiota transplantation, highlighting pharmacokinetic, pharmacodynamic, infectious, and graft-versus-leukemia considerations. Conclusions: Cell- and compartment-resolved metabolite pharmacology may enable tissue-protective strategies that limit GI-GVHD without broadly suppressing antitumor immunity.